In-body power source having high surface area electrode

ABSTRACT

Power sources that enable in-body devices, such as implantable and ingestible devices, are provided. Aspects of the in-body power sources of the invention include a solid support, a first high surface area electrode and a second electrode. Embodiments of the in-power sources are configured to emit a detectable signal upon contact with a target physiological site. Also provided are methods of making and using the power sources of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/527,190, filed Aug. 13, 2009, entitled IN-BODY POWER SOURCE HAVINGHIGH SURFACE AREA ELECTRODE, which application is a 371 application ofInternational Patent Application No. PCT/US2008/053999, filed Feb. 14,2008, which application pursuant to 35 U.S.C. § 119 (e), claims priorityto the filing date of U.S. Provisional Patent Application No. 60/889,870filed on Feb. 14, 2007; the disclosures of which are herein incorporatedby reference.

INTRODUCTION

As medical technology advances, many diagnostic and therapeuticactivities are carried out with increasingly small implantable medicalor ingestible medical devices. Implantable and ingestible medicaldevices can be configured to perform a variety of different functions,including but not limited to: diagnostic functions, e.g., where thedevices include one or more sensors; therapeutic functions, e.g., wherethe devices enable therapeutic action, such as delivery of electricalpulse, delivery of a pharmaceutically active agent; etc.

With implantable and ingestible medical and related technologies, thereis always a desire to make the devices smaller, e.g., to provide forincreased ease of use, etc. To decrease size, individual components ofthe devices must be designed with a reduced overall physical size, andyet maintain functionality.

One type of component that is present in many implantable and ingestibledevices is a power source, e.g., batteries, capacitors, etc. There iscontinued interest in the development of smaller and smaller powersources that nonetheless have adequate and reliable functionality suchthat they can be employed with in-body devices, such as implantable andingestible devices.

SUMMARY

Power sources that enable in-body devices, such as implantable andingestible devices, are provided. Aspects of the in-body power sourcesof the invention include a solid support, a first high surface areaelectrode and a second electrode. Embodiments of the in-power sourcesare configured to emit a detectable signal upon contact with a targetphysiological site. Also provided are methods of making and using thepower sources of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows one embodiment of a battery having a porous cathodeunder-layer according to one embodiment of the invention.

FIG. 2 provides detail of certain implementations of an electroniccircuit of various embodiments of the invention.

DETAILED DESCRIPTION

Power sources that enable in-body devices, such as implantable andingestible devices, are provided. Aspects of the in-body power sourcesof the invention include a solid support, a first high surface areaelectrode and a second electrode. Embodiments of the in-power sourcesare configured to emit a detectable signal upon contact with a targetphysiological site. Also provided are methods of making and using thepower sources of the invention.

In further describing the invention in greater detail, embodiments ofthe in-body power sources and in body devices that include the same arereviewed first, followed by a discussion of systems having devices thatinclude the in-body power sources, and methods of using such devices andsystems. Also reviewed in greater detail below are kits that include thedevices having the in-body power sources of the invention.

In-Body Power Sources and Devices Including the Same

As summarized above, the invention provides power sources configured foruse with in-body devices. An in-body device is a device that isconfigured to be used inside of a living body. Examples of in-bodydevices include, but are not limited to: implantable devices, e.g.,implantable therapeutic devices, implantable diagnostic devices, e.g.,sensors, etc; and ingestible devices, e.g., ingestible event markers(e.g., as described in greater detail below), etc.

In body power sources according to embodiments of the invention includea solid support; a first high surface electrode present on a surface ofsaid solid support; and a second electrode. The solid support may varydepending on the nature of the device with which the in-body powersource is to be employed. In certain embodiments, the solid support issmall, e.g., where it is dimensioned to have a width ranging from about0.01 mm to about 100 mm, e.g., from about 0.1 mm to about 20 mm,including from about 0.5 mm to about 2 mm; a length ranging from about0.01 mm to about 100 mm, e.g., from about 0.1 mm to about 20 mm,including from about 0.5 mm to about 2 mm, and a height ranging fromabout 0.01 mm to about 10 mm, e.g., from about 0.05 mm to about 2 mm,including from about 0.1 mm to about 0.5 mm. The solid support elementmay take a variety of different configurations, such as but not limitedto: a chip configuration, a cylinder configuration, a sphericalconfiguration, a disc configuration, etc, where a particularconfiguration may be selected based on intended application, method ofmanufacture, etc. While the material from which the solid support isfabricated may vary considerably depending on the particular device forwhich the in-body power source is configured for use, in certainembodiments the solid support is made up of a semiconductor material,e.g., silicon. To provide for production of the porous underlayer, e.g.,as described below, portions of the solid support surface may include aconductive material, e.g., metal or metal alloy, such as but not limitedto gold, and the like.

In certain embodiments, the solid support is a semiconductor supportthat includes one or more circuit elements, where in certain embodimentsthe support is an integrated circuit. When present, integrated circuitsinclude a number of distinct functional blocks, i.e., modules. Within agiven solid support, at least some of, e.g., two or more, up to anincluding all of, the functional blocks, e.g., power source, processor,transmitter, etc., may be present in a single integrated circuit. Bysingle integrated circuit is meant a single circuit structure thatincludes all of the different desired functional blocks for the device.In these embodiments, the integrated circuit is a monolithic integratedcircuit (also known as IC, microcircuit, microchip, silicon chip,computer chip or chip) that is a miniaturized electronic circuit (whichmay include semiconductor devices, as well as passive components) thathas been manufactured in the surface of a thin substrate ofsemiconductor material. The integrated circuits of certain embodimentsof the present invention may be hybrid integrated circuits, which areminiaturized electronic circuits constructed of individual semiconductordevices, as well as passive components, bonded to a substrate or circuitboard.

As mentioned above, one type of in-body device in which the powersources of the invention find use is an ingestible event marker. Forease of described, the in-body power sources will now be furtherdescribed in terms of embodiments where the in body power source is partof an identifier of an ingestible event marker. However, as indicatedabove, the in-body power sources of the invention find use in devicesother than ingestible event markers, and therefore in-body power sourcesof the invention are not limited to those configured for use iningestible event markers (IEM).

The identifier of the IEM compositions is one that generates (i.e.,emits) a detectable signal upon contact of the identifier with a targetphysiological sight. The identifiers of the present compositions mayvary depending on the particular embodiment and intended application ofthe composition so long as they are activated (i.e., turned on) uponcontact with a target physiological location, e.g., stomach. As such,the identifier may be an identifier that emits a signal when it contactsa target body (i.e., physiological) site. The identifier may be anycomponent or device that is capable of providing a detectable signalfollowing activation, e.g., upon contact with the target site. Incertain embodiments, the identifier emits a signal once the compositioncomes into contact with a physiological target site, e.g., the stomach.Depending on the embodiment, the target physiological site or locationmay vary, where representative target physiological sites of interestinclude, but are not limited to: a location in the gastrointestinaltract, such as the mouth, esophagus, stomach, small intestine, largeintestine, etc. In certain embodiments, the identifier is configured tobe activated upon contact with fluid in the target site, regardless ofthe particular composition of the target site.

Depending on the needs of a particular application, the signal obtainedfrom the identifier may be a generic signal, e.g., a signal that merelyidentifies that the composition has contacted the target site, or aunique signal, e.g., a signal which in some way uniquely identifies thata particular ingestible event marker from a group or plurality ofdifferent markers in a batch has contacted a target physiological site.As such, the identifier may be one that, when employed with a batch ofunit dosages, e.g., a batch of tablets, emits a signal which cannot bedistinguished from the signal emitted by the identifier of any otherunit dosage member of the batch. In yet other embodiments, theidentifier emits a signal that uniquely identifies that particularidentifier. Accordingly, in certain embodiments the identifier emits aunique signal that distinguishes one class of identifier from othertypes of identifiers. In certain embodiments, the identifier emits aunique signal that distinguishes that identifier from other identifiers.In certain embodiments, the identifier emits a signal that is unique,i.e., distinguishable, from a signal emitted by any other identifierever produced, where such a signal may be viewed as a universally uniquesignal (e.g., analogous to a human fingerprint which is distinct fromany other fingerprint of any other individual and therefore uniquelyidentifies an individual on a universal level). In one embodiment, thesignal may either directly convey information about a given event, orprovide an identifying code, which may be used to retrieve informationabout the event from a database, i.e., a database linking identifyingcodes with compositions.

The identifier may generate a variety of different types of signals,including but not limited to: RF signals, magnetic signals, conductive(near field) signals, acoustic signals, etc. Of interest in certainembodiments are the specific signals described in pending PCTapplication serial no. PCT/US2006/16370 filed on Apr. 28, 2006; thedisclosures of various types of signals in this application beingspecifically incorporated herein by reference. The transmission time ofthe identifier may vary, where in certain embodiments the transmissiontime may range from about 0.1 μsec to about 48 hours or longer, e.g.,from about 0.1 μsec to about 24 hours or longer, such as from about 0.1μsec to about 4 hours or longer, such as from about 1 sec to about 4hours, including about 1 minute to about 10 minutes. Depending on thegiven embodiment, the identifier may transmit a signal once or transmita signal two or more times, such that the signal may be viewed as aredundant signal.

The identifiers of the present compositions may vary depending on theparticular embodiment and intended application of the composition solong as they are activated (i.e., turned on) upon contact with a targetphysiological location, e.g., stomach. As such, the identifier may be anidentifier that emits a signal when it contacts a target body (i.e.,physiological) site. In addition or alternatively, the identifier may bean identifier that emits a signal when interrogated after it has beenactivated. Identifier components of embodiments of the invention have:(a) an activation component; and (b) a signal generation component,where the signal generation component is activated by the activationcomponent to produce an identifying signal, e.g., as described above.

The activation component is a component that activates the signalgeneration element of the identifier to provide a signal, e.g., byemission or upon interrogation, following contact of the compositionwith a target physiological site of interest, such as the stomach. Asreviewed in co-pending PCT application serial no. PCT/US2006/016370,activation of the identifier may be achieved in a number of differentways, where such approaches include, but are not limited to: batterycompletion, battery connection, etc. The different activation approachesdisclosed in this co-pending application may be readily adapted toprovide activation, as described herein, and as such are hereinincorporated by reference in their entirety.

Embodiments of activation elements based on battery completion formatsemploy in body battery sources of the invention, where when activatedthe in-body batter power source includes, a cathode, an anode, and anelectrolyte. In such embodiments, when the cathode and anode come intocontact with stomach fluid, the stomach fluid acts as the electrolytecomponent of the battery, such that the added component of the stomachfluid thus completes the battery.

In certain embodiments, the battery that is employed is one thatcomprises two dissimilar electrochemical materials which constitute thetwo electrodes (e.g., anode and cathode) of the battery. When theelectrode materials come in contact with the body fluid, such as stomachacid or other types of fluid (either alone or in combination with adried conductive medium precursor), a potential difference, i.e., avoltage, is generated between the electrodes as a result of therespective oxidation and reduction reactions occurring at the twoelectrodes (such that a voltaic cell or battery is produced).Accordingly, in embodiments of the invention, in-body power sources areconfigured such that when the two dissimilar materials are exposed tothe target site, e.g., the stomach, the digestive tract, etc., a voltageis generated. The two dissimilar materials in an electrolyte are atdifferent potentials. In certain of these embodiments, the in-bodybattery power source may be viewed as a power source that exploitselectrochemical reaction in an ionic solution such as gastric fluid,blood, or other bodily fluids and some tissues.

The dissimilar materials making up the electrodes can be made of any twomaterials appropriate to the environment in which the identifier will beoperating. The active materials are any pair of materials with differentelectrochemical potentials. For instance, in some embodiments where theionic solution comprises stomach acids, electrodes may be made of anoble metal (e.g., gold, silver, platinum, palladium or the like) sothat they do not corrode prematurely. Alternatively, the electrodes canbe fabricated of aluminum or any other conductive material whosesurvival time in the applicable ionic solution is long enough to allowthe identifier to perform its intended function. Suitable materials arenot restricted to metals, and in certain embodiments the pairedmaterials are chosen from metals and non-metals, e.g., a pair made up ofa metal (such as Mg) and a salt (such as CuI). With respect to theactive electrode materials, any pairing of substances—metals, salts, orintercalation compounds—with suitably different electrochemicalpotentials (voltage) and low interfacial resistance are suitable.

A variety of different materials may be employed as the batteryelectrodes. In certain embodiments, electrode materials are chosen toprovide for a voltage upon contact with the target physiological site,e.g., the stomach, sufficient to drive the signal generation element ofthe identifier. In certain embodiments, the voltage provided by theelectrode materials upon contact of the metals of the power source withthe target physiological site is 0.001 V or higher, including 0.01 V orhigher, such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5volts or higher, and including 1.0 volts or higher, where in certainembodiments, the voltage ranges from about 0.001 to about 10 volts, suchas from about 0.01 to about 10 V.

Materials and pairings of interest include, but are not limited to thosereported in Table 1 below.

TABLE 1 Anode Cathode Metals Magnesium, Zinc Sodium (†), Lithium (†)Iron and alloys thereof, e.g., Al and Zn alloys of Mg Salts Coppersalts: iodide, chloride, bromide, sulfate, formate, (other anionspossible) Fe³⁺ salts: e.g. orthophosphate, pyrophosphate, (other anionspossible) Oxygen or hydrogen (††) on platinum, gold or other catalyticsurfaces Intercalation Graphite with Li, Vanadium oxide compounds K, Ca,Na, Mg Manganese oxide (†) Protected anodes: certain high energy anodematerial such as Li, Na, and other alkali metals are unstable in theirpure form in the presence of water or oxygen. These may however be usedin an aqueous environment if stabilized. One example of thisstabilization is the so-called “protected lithium anode” developed byPolyplus Corporation (Berkeley, CA), where a polymer film is depositedon the surface of lithium metal to protect it from rapid oxidation andallow its use in aqueous environment or air ambient. (Polyplus has IPpending on this). (††) Dissolved oxygen can also serve as a cathode. Inthis case, the dissolved oxygen in the bodily fluids would be reduced toOH— at a suitable catalytic surface such at Pt or gold. Also of interestdissolved hydrogen in a hydrogen reduction reaction.

In certain embodiments, one or both of the metals may be doped with anon-metal, e.g., to enhance the voltage output of the battery.Non-metals that may be used as doping agents in certain embodimentsinclude, but are not limited to: sulfur, iodine and the like.

In certain embodiments, the electrode materials are cuprous iodine (CuI)or cuprous chloride (CuCl) as the cathode and magnesium (Mg) metal ormagnesium alloy as the anode. Embodiments of the present invention useelectrode materials that are not harmful to the human body.

As summarized above, in-body power sources of the invention, such asbatteries that include electrodes of two dissimilar materials (asreviewed immediately above) include at least one a high surface areaelectrode, e.g., a high surface area cathode and/or high surface areaanode. By high surface area electrode is meant an electrode having asurface area that is about 2-fold or greater, such at about 10-fold orgreater, than the area of the surface of a solid support that is coveredby the electrode in the power source, e.g., battery. In certainembodiments, the surface area of the electrode ranges from about 0.01mm² to about 100 mm², such as from about 0.1 mm² to about 50 mm² andincluding from about 1 mm² to about 10 mm². In certain embodiments, thehigh surface area electrode is obtained by having an electrode that ismade up of an active electrode material (e.g., where illustrative activecathode and anode materials are provided above) present on a porousunder-layer. In certain embodiments, all of the electrodes are highsurface area electrodes, while in other embodiments only some of theelectrodes, e.g., one of the electrodes, is a high surface areaelectrode.

Depending on the particular embodiment, the cathode and anode may bepresent on the same support or different supports, e.g., where two ormore different supports are bonded together to produce the batterystructure, e.g., as is present in a “flip-chip” embodiment. Similarly,the number of cathodes and anodes in a given battery may vary greatlydepending on the embodiment, e.g., where a given embodiment may includea single battery having one anode and cathode, a single battery havingmultiple anodes and/or cathodes, or two or more distinct batteries eachmade up of one or more cathodes and/or anodes. Battery configurations ofinterest include, but are not limited to, those disclosed in PCTapplication serial no. PCT/US2006/016370 filed on Apr. 28, 2006 andentitled PHARMA-INFORMATICS SYSTEM; PCT application serial no.PCT/US2007/022257 filed on Oct. 17, 2007 and entitled IN-VIVO LOWVOLTAGE OSCILLATOR FOR MEDICAL DEVICES; PCT application serial no.PCT/US2007/82563 filed on Oct. 25, 2007 and entitled CONTROLLEDACTIVATION INGESTIBLE IDENTIFIER; U.S. patent application Ser. No.11/776,480 filed Jul. 11, 2007 entitled ACOUSTIC PHARMA INFORMATICSSYSTEM; and PCT application serial no. PCT/US2008/52845 filed on Feb. 1,2008 and entitled INGESTIBLE EVENT MARKER SYSTEMS; the disclosures ofwhich applications (and particularly battery configurations disclosedtherein) are herein incorporated by reference.

FIG. 1 provides a schematic illustration of battery power sourceaccording to an embodiment of the invention that includes a high surfacearea electrode, and specifically a high surface area cathode. Thebattery 100 shown in FIG. 1 includes a solid support 120 having an uppersurface 140. Present on the upper surface 140 is cathode 160 and anode180. Cathode 160 includes porous under-layer 150 and active cathodematerial 170. Each of these elements is now described in greater detailbelow. While the embodiment depicted is where the cathode includes aporous under-layer, in certain embodiments it is the anode that includesa porous underlay, while in yet other embodiments both a cathode andanode have the porous under-layer. Both the cathode and anode arepresent on a surface of a solid support. In certain embodiments such asthat shown in FIG. 1 , the two electrodes are present on the samesurface of the solid support. In yet other embodiments, the twoelectrodes may be present on different surfaces of the support, e.g.,opposite surfaces of the support.

The porous under-layer 150 is a layer that mechanically supports theactive electrode (e.g., cathode) material 170, improves adhesion and/orincreases the surface area of the electrode, and provides for currentpassage between the cathode material and elements, e.g., circuitry,present on the solid support 120 (described in greater detail below).The porous under-layer may be fabricated from a variety of differentmaterials, such as conductive materials, e.g., copper, titanium,aluminum, graphite, gold, platinum, iridium, etc., where the materialsmay be pure materials or materials made up of two or more elements,e.g., as found in alloys, etc. With respect to a cathode, materials ofinterest for a cathode porous underlayer include, but are not limitedto: Au, Cu, Pt, Ir, Pd, Rh, Ru, as well as binary and ternary alloysthereof. With respect to a anode, materials of interest for an anodeporous underlayer include, but are not limited to: Ti and alloys thereof(e.g., Ti—W, Ti—Cr, TiN), W, W—C, etc. The thickness of the under-layermay vary, where in certain embodiments the thickness ranges from about0.01 to about 100 μm, such as from about 0.05 to about 50 μm andincluding from about 0.01 to about 10 μm. The dimensions of the porousunder-layer with respect to length and width on the surface of the solidsupport may or may not be coextensive with the same dimensions of theactive cathode material, as desired.

As summarized above, the under-layer may be rough or porous. Theporosity or roughness of the under-layer may vary, so long as it impartsthe desired surface area to the electrode, e.g., cathode. In certainembodiments, the porosity or roughness of the under-layer is chosen toprovide an effective surface area enhancement of about 1.5 times or moreto about 1000 times or more, e.g., from about 2 to about 100 time ormore, such as from about 2 to about 10 times or more, greater than thatobtained from a comparable electrode that lacks the porous underlayer.Surface area enhancement can be determined by comparing theelectrochemical capacitance or cyclic voltammogram of the rough orporous electrode with that of a smooth electrode of the same material.Roughness may also be determined by other techniques, such as atomicforce microscopy (AFM), electron microscopy, electrochemical impedancespectroscopy or Brunauer-Emmett-Teller (BET) analysis.

The porous cathode under-layer may be produced using any convenientprotocol. In certain embodiments, planar processing protocols areemployed. Planar processing techniques, such as Micro-Electro-MechanicalSystems (MEMS) fabrication techniques, including surface micromachiningand bulk micromachining techniques, may be employed. Depositiontechniques that may be employed in certain embodiments of fabricatingthe structures include, but are not limited to: electrodeposition (e.g.,electroplating), cathodic arc deposition, plasma spray, sputtering,e-beam evaporation, physical vapor deposition, chemical vapordeposition, plasma enhanced chemical vapor deposition, etc. Materialremoval techniques included, but are not limited to: reactive ionetching, anisotropic chemical etching, isotropic chemical etching,planarization, e.g., via chemical mechanical polishing, laser ablation,electronic discharge machining (EDM),electrodissolution/electropolishing (a metal is deposited, thenselective areas are dissolved to make it rough and porous), etc. Anotherprotocol of interest is electroless plating as a deposition method. Inthese deposition protocols, metal is deposited out of solution by areducing agent. The deposited metal layer can be used to coat an alreadyexisting rough nonconductive/poorly conductive surface layer orparticles such as carbon, alumina, polymers, zeolite, silicon oxide,amorphous carbon and nanotubes. The nonconductive layer can be depositedvia any suitable planar processing method, such as cathodic arc,electrophoretic deposition, or a paste/glue containing particles. Alsoof interest are lithographic protocols. Of interest in certainembodiments is the use of planar processing protocols, in whichstructures are built up and/or removed from a surface or surfaces of aninitially planar substrate using a variety of different material removaland deposition protocols applied to the substrate in a sequentialmanner. Illustrative fabrication methods of interest are described ingreater detail in copending PCT application serial no.PCT/US2006/016370; the disclosure of which is herein incorporated byreference.

For the porous under-layer, in certain embodiments an electrodepositionprotocol is employed. Where the porous cathode under-layer comprises ametal(s), electroplating (electrodeposition of metals) may be employed.In certain embodiments, the electroplating protocol employed is one inwhich the current density and/or agitation of the solution is selectedso as to impart the desired roughness or porosity to the depositedporous cathode under-layer. In certain embodiments, the metal, e.g.,copper, film is deposited in an electroplating bath at the mass-transferlimit. The phrase “mass transfer limit” means that the current densityis optimized along with the metal ion concentration in the bath and theflow rate of the bath, such that depositing occurs at substantially themaximum limit at which metal ions can arrive at the surface. Depositionat the mass transfer limit yields, in certain embodiments, a dendriticform of deposited material. Depending on the particular metal and ionconcentration thereof, the current density may vary. In certain of theembodiments, the selected current density ranges from about 5 to about2000 mAmps/cm², such as from about 50 to about 400 mAmps/cm², e.g.,about 200 mAmps/cm². Plate up may be carried out in a suitable platingcell, such as a plating tank with agitation, a paddle cell, or afountain cell. The fluid flow may be selected in conjunction with theapplied current density to achieve the desired porosity or roughness. Ina plating tank with a rotary mixer, the stirring rate may be betweenabout 0 and about 200 rpm, such as between about 50 to about 500 rpm.With respect to the metal ion concentration, a relatively lower metalion concentration may be employed to obtain a rough deposit at a lowercurrent density while relatively higher ion concentration may beemployed to obtain a rough deposit at a higher current density. Incertain embodiments, the metal ion concentration ranges from 0.001 mol/Lto 4 mol/L, such as from 0.05 mol/L to 1 mol/L. Flow rate employedduring deposition also impacts the nature of the film that is deposited.Lower flow rates can be used lower current densities.

Where desired, various additives may be included in the electroplatingfluid to enhance the desired porosity. Additives that may be included inthe solution include, but are not limited to: organic acids, e.g.,acetic acid, citric acid, e.g., polymers, e.g., PEG, etc. The plating upsolution may also contain alcohols, e.g., ethanol), amines and thiols(e.g., thiourea). Typical copper plating bath compositions (such asacidic, e.g., sulfuric acid/copper sulfate) and alkaline (e.g.,pyrophosphate or chromate solutions) may also be used. Where polymersare added, the polymers may be linear or branched water-solublepolymers, such as a poly(alkylene glycol), such as poly(ethylene glycol)(PEG). Other related polymers are also suitable for use in the practiceof this invention and that the use of the term PEG or poly(ethyleneglycol) is intended to be inclusive and not exclusive in this respect.In some embodiments, the polymer has from 2 to about 300 termini. Insome embodiments, the polymer is clear, colorless, odorless, soluble inwater, stable to heat, inert to many chemical agents, does not hydrolyzeor deteriorate, and is nontoxic. In some embodiments, the polymer isbiocompatible, which is to say that the polymer is capable ofcoexistence with living tissues or organisms without causing harm. Insome embodiments, the polymer is non-immunogenic, which is to say thatthe polymer does not produce an immune response in the body. In someembodiments, the polymer is a PEG comprising the formulaRa—(CH₂CH₂O)m-CH₂CH₂—, where m is from about 3 to about 4000, or fromabout 3 to about 2000, and Ra is a hydrogen, —OH, CH₃—O—, CH₂CH₂—O- orCH₃CH₂CH₂—O—. The polymer can be linear or branched. In someembodiments, a branched polymer has a central branch core moiety and aplurality of linear polymer chains linked to the central branch core.PEG includes branched forms that can be prepared by addition of ethyleneoxide to various polyols, such as glycerol, pentaerythritol andsorbitol. The branched PEGs can be represented in general form asRb(-PEG-OH)n in which Rh represents the core moiety, such as glycerol orpentaerythritol, and n represents the number of arms and is from 2 to300. In some embodiments, the PM is a linear or branched PEG. Suitablepolymers that can be employed include, but are not limited to,poly(alkylene glycol), such as poly(ethylene glycol) (PEG) andpolypropylene glycol) (PPG), copolymers of ethylene glycol and propyleneglycol and the like, poly(oxyethylated polyol), poly(olefinic alcohol),poly(vinylpyrrolidone), poly(hydroxypropylmethacrylarnide),poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene,polyoxazoline, and copolymers, terpolymers, derivatives and mixturesthereof. The molecular weight of each chain of the polymer can vary inthe range of from about 100 Da to about 100,000 Da, or from about 6,000Da to about 80,000 Da. Suitable PEGs include, but are not limited to,PEG(100), PEG(200), PEG(300), PEG(400), PEG(600), PEG(1000), PEG(1500),PEG(2000), PEG(3000), PEG(3350), PEG(4000), PEG(5000), PEG(6000),PEG(8000), and PEG(10000), and methoxy and ethoxy derivatives thereof,and any PEG having a molecular size within and inclusive of any of theabove indicated molecular weights. The polymer component may besynthesized using any convenient protocol or purchased from a commercialsource, as desired. Suitable PEGs are commercially available from manysources, such as Sigma-Aldrich Corp. (St. Louis, Mo.).

Additives of interest include, but are not limited to, accelerator,suppressors, wetting agents, levelers and bath stabilizers. Acceleratorsof interest include, but are not limited to: thiols, such as thioureaand 3-sulfopropyldisulfide, where accelerators of interest, either bythemselves or in combination with other additives, accelerate metal,e.g., copper, deposition rate. In certain embodiments, the acceleratoradditive is present at a concentration ranging from 1 ppB to 1000 ppm,such as 10 ppb to 500 ppm. In certain embodiments, the concentration ofadditive is employed in combination with a flow rate the provides fordendritic nodules that grow at a substantially exponential rate, e.g.,where the end of the dendrite is present in a relatively richaccelerator environment and the opposite end of the dendrite proximal tothe surface is present in a relatively poor accelerator environment. Incertain of these embodiments, the flow rate is set to have a certaindiffusion layer thickness which provides for this type of growth, wherethe diffusion layer thickness may range from 0.01 to 500 μm, such as 1to 100 μm.

In certain embodiments, accelerating additives are employed incombination with suppressing additives. Suppressing additives ofinterest are compounds that physically block the surface of the metal,where such additives include, but are not limited to: polyetheleneglycol, amino compounds and organic compounds. By physically blockingthe surface of the solid support, growth at the surface distal ends ofthe deposited structures may be enhanced relative to growth at thesurface proximal ends.

In these embodiments, concentrations and types of accelerating additivesmay be employed that eliminate the impact of suppressing additives,where the accelerators dislodge the suppressors. In certain of theseembodiments, a solution is employed that has a suppressing additive andan accelerating additive, where the concentration of the suppressingadditive is mass-transfer limited. Any part of the solution that gets alittle bit of a nodule going will reach into a higher concentrationregion of accelerant and then will grow exponentially to provide adesired amount of roughness. In these embodiments, the area close to thesurface is heavily suppressed by the suppressor agent. The parts of thegrowing nodules that stick up into the solution come into contact withan accelerating agent that can come in and dislodge the suppressingagent, and provide the desired dendritic format or nodules.

An alternative to employing a suppressing agent, e.g., as describedabove, is to employ a protocol that includes co-evolution of gas, whereblocking gas bubbles are produced at the surface of the solid supportduring deposition. In these embodiments, the deposition conditions arechosen that generate a gas, e.g., hydrogen gas, at he surface of thesolid support upon which the metal is being deposited. Where desired,the size of the bubbles that are produced in these protocols may bemodulated by employing a surface tension agent, e.g., acetic acid,polyethylene glycol, or other agents that control the wetting propertiesin a manner that provides for bubbles of desired dimension. Relativelyless wetting agent can be employed to provide for larger, e.g., micron,sized pores, while relatively more wetting agent can be employed forsmaller sized pores.

The gas coevolution protocol may be employed with appropriateaccelerator agents in a manner analogous that described above withrespect to suppressor agents, as both approaches physically block thesurface of the solid support and the presence of the accelerator may beemployed to enhance growth at the surface distal ends of the depositedstructures. Accordingly, when current to the entire surface of the solidsupport, the metal, e.g., copper will preferentially plate where thereis accelerating species as opposed to in the regions, e.g., valleysbetween deposited structure, where there is no accelerating species,e.g., because of presence of physical blocking agent, such as a bubbleor suppressor species.

In yet another embodiment, a self-assembled monolayer, or anelectro-grafted layer, which is an organic, diazonium containing speciesthat can actually covalently bond to the surface of the solid supportmay be employed. In manner similar to the bubbles and suppressorsdescribed above, such deposited species can also physically block thesurface to modulate the form of the plated structures and provide thedesired porous structure. By controlling the concentration of the nucleiof the electrographic layer, or the density of the self-assembled monolayer, one can modulate the nature of the deposited metal structures. Incertain embodiments, these protocols are employed where a metaldifferent from that of the solid support is being deposited on the solidsupport. In certain embodiments, a masking approach is employed tofurther modulate the nature of the deposited structures on the surfaceof the solid support.

In yet other embodiments, a cathodic arc deposition protocol is employedto produce the desired porous cathode under-layer. In such protocols, acathodic arc generated metallic ion plasma is contacted with a surfaceof a substrate under conditions sufficient to produce the desiredstructure of the porous cathode under-layer, e.g., as described above.The cathodic arc generated ion plasma beam of metallic ions may begenerated using any convenient protocol. In generating an ion beam bycathodic arc protocols, an electrical arc of sufficient power isproduced between a cathode and one or more anodes so that an ion beam ofcathode material ions is produced. Prior to deposition of the cathodicarc metal, a seed metal layer is produced from at least one, but oftentwo or more, conformal metal underlayers. These underlayers start with athin adhesion layer that contains metals including but not limited toTiN, Ti, W, Cr or alloys of these metals. This first metal layerimproves adhesion of the thicker cathodic arc metal and may be sealedwith a noble metal that includes, but is not limited to, Au, Pt, Ag, Cu,Pt, Ir, Pd, Rh, or Ru or alloys of these metals. The cap metal seals theadhesion metal chemically and is chosen to also adhere well to thethicker metal deposited by the cathodic arc process. The cathodic arccan be run in a variety of conditions, including but not limited tohigher pressure of inert gas (gas could be Ar, Ne, He, Xe or a simplemixture of these; pressures can range over 50 mT up to 1000 mT) and aneutral (unbiased) target. In the case of a higher pressure and aneutral target, this suppresses small ionized metal particles in favorof larger macro particles at the target surface during film growth,resulting in a film that can have peak-to-peak roughness values rangingfrom 0.2 to 10 times the average deposited film thickness. Films growncan be as thin as 0.25 um and up to 25 um, and in certain embodimentsare in the range of 3 to 10 um thick before they achieve a desiredroughness for the underlying electrode structure. Other convenientprotocols for producing a structure via cathodic arc deposition may beemployed, where protocols known in the art which may be adapted for usein the present invention include, but are not limited to those describedin U.S. Pat. Nos. 6,929,727; 6,821,399; 6,770,178; 6,702,931; 6,663,755;6,645,354; 6,608,432; 6,602,390; 6,548,817; 6,465,793; 6,465,780;6,436,254; 6,409,898; 6,331,332; 6,319,369; 6,261,421; 6,224,726;6,036,828; 6,031,239; 6,027,619; 6,026,763; 6,009,829; 5,972,185;5,932,078; 5,902,462; 5,895,559; 5,518,597; 5,468,363; 5,401,543;5,317,235; 5,282,944; 5,279.723; 5,269,896; 5,126,030; 4,936,960; andPublished U.S. Application Nos.: 2005/0249983; 2005/0189218;2005/0181238; 2004/0168637; 2004/0103845; 2004/0055538; 2004/0026242;2003/0209424; 2002/0144893; 2002/0140334 and 2002/0139662; thedisclosures of which are herein incorporated by reference. Suchprotocols are of interest in the deposition of a variety of differentmaterials, e.g., copper, titanium, aluminum, etc. Additional cathodicarc protocols and structures produced thereby include, but are notlimited to, those described in published PCT application No. WO2007/149546 titled IMPLANTABLE MEDICAL DEVICES COMPRISING CATHODIC ARCPRODUCED STRUCTURES, the disclosure of which is herein incorporated byreference.

In yet other embodiments an electrophoretic deposition protocol may beemployed. Electrophoretic deposition (EPD) is a term for a broad rangeof industrial processes which includes electrocoating, electrophoreticcoating, or electrophoretic painting. In EPD, colloidal particlessuspended in a liquid medium migrate under the influence of an electricfield (electrophoresis) and are deposited onto a conductive surface. Allcolloidal particles that can be used to form stable suspensions and thatcan carry a charge can be used in electrophoretic deposition. Thisincludes material classes such as polymers, pigments, dyes, ceramics andmetals. For example, where the material to be deposited is graphite, asuspension of graphite particles may be produced, where surfactants maybe included in the suspension to impart a desired charge to the graphiteparticles. Sizes for the graphite particles may vary, and in certainembodiments may range from about 0.1 to about 100 μm, such as from about0.1 to about 2 μm. Any convenient surfactant may be includes that iscapable of imparting the desired charge to the graphite particles insuspension, including ionic and non-ionic surfactants. An electric fieldmay then be applied to the suspension, where the applied electric fieldis sufficient to cause the graphite particles to migrate to the surfaceof the support and be deposited in the form of the desired porousunder-layer.

In yet other embodiments, the solid support surface is electrochemicallymodified, e.g., via electrochemical dissolution, where portions of thesurface are selectively removed to provide for the desired porousstructure. For example, an anodic potential may be applied to a metalsurface to dissolve the metal surface. Such an approach may be employedin combination with a patterning photo-resist layer and/or withadditives to generate a desired roughness or pattern of nodules on thesurface. In certain of these embodiments, a metal layer is firstdeposited, e.g., by any convenient deposition protocol. Next, additivesand/or masking (e.g., photoresist) is employed to selectively dissolvecertain areas of the surface and make the surface rough.

In certain embodiments, a metal code position and dissolution approachis employed. In these embodiments, two metals are simultaneouslydeposited, e.g., via cathodic arc, evaporation, sputtering, etc.) tomake a composite layer, where the metals are (1) an inert electrodemetal, such as Pt, PtIr, Ir, Au, or Cu and (2) a highly oxidizable andsoluble metal, such as Mg, Zn, Li. The resulting deposited layer is acomposite, consisting of mostly metal 1, but with isolated domains ofmetal 2. The layer is then immersed in an electrolytic solution (e.g., asolvent such as water or an organic acid (such as sulfuric, nitric orhydrochloric acids), bases (such as NaOH, aluminum etchant), neutralsalts (such as NaCl, KCl, CuSO₄, magnesium, lithium, zinc salts), ororganic additives and surfactants (such as polyethylene glycol). Uponimmersion, metal 2 dissolves away leaving behind a film of metal 1 thatincludes pores. The size of the pores will be that of the particles ofmetal (2). In certain embodiments, e.g., where one does not wish toleave any of metal 2 behind inside the film, the second metal'sdeposition conditions (deposition current, filtering, cathodetemperature, etc) are set to yield particles that are on the order ofthe total desired film thickness. The first metal particles may beselected to be smaller and more compact than those of the second metal.Cathodic arc is particularly suitable for the composite film depositionbecause it allows deposition of particles with controlled particle size.The dissolution step may be carried out with an applied current (anodicdissolution), or it can be done without an applied current in which caseit is a result of the chemical reaction between metal 2 and solutioncomponents and/or a galvanic couple between metal 1 and metal 2 thatforces metal 2 to corrode. The above approach can also be applied tonon-metallic rough films, e.g., any pair of materials deposited viacathodic arc where one of them can be selectively dissolved or etchedaway leaving behind a porous layer. Also, the above approach is notlimited to two metals, i.e. 2 or more metals (or alloys) can be includedin the composite film.

Present on top of the porous under-layer is the active electrode (e.g.,cathode) material. As reviewed above, the active electrode material maycomprise a variety of different materials. Where the electrode is acathode, in certain embodiments, the cathode material includes copper,where of particular interest in certain embodiments are cuprous iodide(CuI) or cuprous chloride (CuCl) as the cathode material. Where desired,e.g., to enhance voltage of the battery, the active material may bedoped with additional elements, e.g., sulfur, etc.

The active cathode material may be provided onto the porous under-layerusing any convenient protocol. In certain embodiments, a depositionprotocol is employed, such as electrodeposition, e.g., electroplating,or evaporation, e.g., chemical vapor deposition.

Also present in the battery is at least one anode. As reviewed above,the anode material may comprise a variety of different materials. Incertain embodiments, the anode material includes magnesium (Mg) metal ormagnesium alloy. The active anode material may be provided onto theporous under-layer using any convenient protocol. In certainembodiments, a deposition protocol is employed, such aselectrodeposition, e.g., electroplating, or evaporation, e.g., chemicalvapor deposition.

As reviewed above, in certain embodiments, the solid support 120 is acircuitry support element. The circuitry support element may take anyconvenient configuration, and in certain embodiments is an integratedcircuit (IC) chip. The surface upon which the electrode elements arepositioned may be the top surface, bottom surface or some other surface,e.g., side surface, as desired, where in certain embodiments the surfaceupon which the electrode elements are at least partially present is atop surface of an IC chip.

In addition to the battery component of the identifier, described above,identifiers of the invention also include a signal generation component.The signal generation component of the identifier element is a structurethat, upon activation by the activation component, emits a detectablesignal, e.g., that can be received by a receiver, e.g., as described ingreater detail below. The signal generation component of certainembodiments can be any convenient device that is capable of producing adetectable signal and/or modulating transduced broadcast power, uponactivation by the activation component. Detectable signals of interestinclude, but are not limited to: conductive signals, acoustic signals,etc. As reviewed above, the signals emitted by the signal generator maybe generic or unique signals, where representative types of signals ofinterest include, but are not limited to: frequency shift coded signals;amplitude modulation signals; frequency modulation signals; etc.

In certain embodiments, the signal generation element includescircuitry, as developed in more detail below, which produces orgenerates the signal. The type of circuitry chosen may depend, at leastin part, on the driving power that is supplied by the power source ofthe identifier. For example, where the driving power is 1.2 volts orabove, standard CMOS circuitry may be employed. In other embodimentswhere the driving power ranges from about 0.7 to about 1.2 V,sub-threshold circuit designs may be employed. For driving powers ofabout 0.7 V or less, zero-threshold transistor designs may be employed.

In certain embodiments, the signal generation component includes avoltage-controlled oscillator (VCO) that can generate a digital clocksignal in response to activation by the activation component. The VCOcan be controlled by a digital circuit, which is assigned an address andwhich can control the VCO with a control voltage. This digital controlcircuit can be embedded onto a chip that includes the activationcomponent and oscillator. Using amplitude modulation or phase shiftkeying to encode the address, an identifying signal is transmitted.

The signal generation component may include a distinct transmittercomponent that serves to transmit the generated signal to a remotereceiver, which may be internal or external to the patient, as reviewedin greater detail below. The transmitter component, when present, maytake a number of different configurations, e.g., depending on the typeof signal that is generated and is to be emitted. In certainembodiments, the transmitter component is made up of one or moreelectrodes. In certain embodiments, the transmitter component is made upof one or more wires, e.g., in the form of antenna(e). In certainembodiments, the transmitter component is made up of one or more coils.As such, the signal transmitter may include a variety of differenttransmitters, e.g., electrodes, antennas (e.g., in the form of wires)coils, etc. In certain embodiments, the signal is transmitted either byone or two electrodes or by one or two wires. A two-electrodetransmitter is a dipole; a one electrode transmitter forms a monopole.In certain embodiments, the transmitter only requires one diode drop ofpower. In some embodiments, the transmitter unit uses an electric dipoleor electric monopole antenna to transmit signals.

FIG. 2 shows the detail of one implementation of an electronic circuitthat can be employed in an identifier according to the presentinvention. On the left side are the two battery electrodes, metal 1 andmetal 2 (32 and 33). These metals, when in contract with an electrolyte(produced upon contact with target site fluid, either alone or incombination with dried conductive medium precursor, as reviewed above),form a battery that provides power to an oscillator 61, in this caseshown as a schematic. The metal 1 32 provides a low voltage, (ground) tothe oscillator 61. Metal 2 33 provides a high voltage (V_(hign)) to theoscillator 61. As the oscillator 61 becomes operative, it generates aclock signal 62 and an inverted clock signal 63, which are opposites ofeach other. These two clock signals go into the counter 64 which simplycounts the number of clock cycles and stores the count in a number ofregisters. In the example shown here, an 8 bit counter is employed.Thus, the output of counter 64 begins with a value of “00000000,”changes to “00000001” at the first clock cycle, and continues up to“11111111.” The 8-bit output of counter 64 is coupled to the input of anaddress multiplexer (mux) 65. In one embodiment, mux 65 contains anaddress interpreter, which can be hard-wired in the circuit, andgenerates a control voltage to control the oscillator 61. Mux 65 usesthe output of counter 64 to reproduce the address in a serial bitstream, which is further fed to the signal-transmission driving circuit.Mux 65 can also be used to control the duty-cycle of the signaltransmission. In one embodiment, mux 65 turns on signal transmissiononly one sixteenth of the time, using the dock counts generated bycounter 64. Such a low duty cycle conserves power and also allows otherdevices to transmit without jamming their signals. The address of agiven chip can be 8 bits, 16 bits or 32 bits. Where desired, more than 8bits may be used in a product, e.g., where the identifiers are employedwith different types of pharmaceutical agents and each pharmaceutical isdesired to have its own specific address.

According to one embodiment, mux 65 produces a control voltage, whichencodes the address serially and is used to vary the output frequency ofoscillator 61. By example, when the control voltage is low, that is,when the serial address bit is at a 0, a 1 megahertz signal is generatedby the oscillator. When the control voltage is high, that is, when theaddress bit is a 1, a 2 megahertz signal is generated the oscillator.Alternately, this can be 10 megahertz and 20 megahertz, or a phase shiftkeying approach where the device is limited to modulating the phase. Thepurpose of mux 65 is to control the frequency of the oscillator or an ACalternative embodiment of the amplified signal of oscillation.

The outputs of mux 65 are coupled to electrode drive 66 which can drivethe electrodes to impose a differential potential to the solution, drivean oscillating current through a coil to generate a magnetic signal, ordrive a single electrode to push or pull charge to or from the solution.In this manner, the device broadcasts the sequence of 0's and 1's whichconstitute the address stored in mux 65. That address would be broadcastrepeatedly, and would continue broadcasting until metal 1 or metal 2 (32and 33) is consumed and dissolved in the solution, when the battery nolonger operates.

Other configurations for the signal generation component are of coursepossible. Other configurations of interest include, but are not limitedto, those described in PCT application serial no. PCT/US2006/016370filed on Apr. 28, 2006 and entitled PHARMA-INFORMATICS SYSTEM; PCTapplication serial no. PCT/US2007/022257 filed on Oct. 17, 2007 andentitled 1N-VIVO LOW VOLTAGE OSCILLATOR FOR MEDICAL DEVICES; PCTapplication serial no. PCT/US2007/082563 filed on Oct. 25, 2007 andentitled CONTROLLED ACTIVATION INGESTIBLE IDENTIFIER; U.S. patentapplication Ser. No. 11/776,480 filed Jul. 11, 2007 entitled ACOUSTICPHARMA INFORMATICS SYSTEM; and PCT application serial no.PCT/US2008/052845 filed on Feb. 1, 2008 and entitled INGESTIBLE EVENTMARKER SYSTEMS; the disclosures of which applications (and particularlysignal generation components thereof) are herein incorporated byreference.

The identifiers may be fabricated using any convenient processingtechnology. In certain embodiments, planar processing protocols areemployed to fabricate power sources having surface electrodes, where thesurface electrodes include at least an anode and cathode at leastpartially on the same surface of a circuitry support element. In certainembodiments, planar processing protocols are employed in a wafer bondingprotocol to produce a battery source. Planar processing techniques, suchas Micro-Electro-Mechanical Systems (MEMS) fabrication techniques,including surface micromachining and bulk micromachining techniques, maybe employed. Deposition techniques that may be employed in certainembodiments of fabricating the structures include, but are not limitedto: electrodeposition (e.g., electroplating), cathodic arc deposition,plasma spray, sputtering, e-beam evaporation, physical vapor deposition,chemical vapor deposition, plasma enhanced chemical vapor deposition,etc. Material removal techniques included, but are not limited to:reactive ion etching, anisotropic chemical etching, isotropic chemicaletching, planarization, e.g., via chemical mechanical polishing, laserablation, electronic discharge machining (EDM), etc. Also of interestare lithographic protocols. Of interest in certain embodiments is theuse of planar processing protocols, in which structures are built upand/or removed from a surface or surfaces of an initially planarsubstrate using a variety of different material removal and depositionprotocols applied to the substrate in a sequential manner. Illustrativefabrication methods of interest are described in greater detail incopending PCT application serial no. PCT/US2006/016370; the disclosureof which is herein incorporated by reference.

Optional Physiologically Acceptable Carrier Component

Identifiers of the invention that include in-body power sources asdescribed above may be present in (i.e., combined with) aphysiologically acceptable carrier component, e.g., a composition orvehicle that aids in ingestion of the identifier and/or protects theidentifier until it reaches the target site of interest. Byphysiologically acceptable carrier component” is meant a composition,which may be a solid or fluid (e.g., liquid), which has is ingestible.

Common carriers and excipients, such as corn starch or gelatin, lactose,dextrose, sucrose, microcrystalline cellulose, kaolin, mannitol,dicalcium phosphate, sodium chloride, and alginic acid are of interest.Disintegrators commonly used in the formulations of the inventioninclude croscarmellose, microcrystalline cellulose, corn starch, sodiumstarch glycolate and alginic acid.

A liquid composition may comprise a suspension or solution of thecompound or pharmaceutically acceptable salt in a suitable liquidcarrier(s), for example, ethanol, glycerine, sorbitol, non-aqueoussolvent such as polyethylene glycol, oils or water, with a suspendingagent, preservative, surfactant, wetting agent, flavoring or coloringagent. Alternatively, a liquid formulation can be prepared from areconstitutable powder. For example, a powder containing activecompound, suspending agent, sucrose and a sweetener can be reconstitutedwith water to form a suspension; and a syrup can be prepared from apowder containing active ingredient, sucrose and a sweetener.

A composition in the form of a tablet or pill can be prepared using anysuitable pharmaceutical carrier(s) routinely used for preparing solidcompositions. Examples of such carriers include magnesium stearate,starch, lactose, sucrose, microcrystalline cellulose and binders, forexample, polyvinylpyrrolidone. The tablet can also be provided with acolor film coating, or color included as part of the carrier(s). Inaddition, active compound can be formulated in a controlled releasedosage form as a tablet comprising a hydrophilic or hydrophobic matrix.

“Controlled release”, “sustained release”, and similar terms are used todenote a mode of active agent delivery that occurs when the active agentis released from the delivery vehicle at an ascertainable andcontrollable rate over a period of time, rather than dispersedimmediately upon application or injection. Controlled or sustainedrelease may extend for hours, days or months, and may vary as a functionof numerous factors. For the pharmaceutical composition of the presentinvention, the rate of release will depend on the type of the excipientselected and the concentration of the excipient in the composition.Another determinant of the rate of release is the rate of hydrolysis ofthe linkages between and within the units of the polyorthoester. Therate of hydrolysis in turn may be controlled by the composition of thepolyorthoester and the number of hydrolysable bonds in thepolyorthoester. Other factors determining the rate of release of anactive agent from the present pharmaceutical composition includeparticle size, acidity of the medium (either internal or external to thematrix) and physical and chemical properties of the active agent in thematrix.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, for example, by incorporation of activecompound and excipients into a hard gelatin capsule. Alternatively, asemi-solid matrix of active compound and high molecular weightpolyethylene glycol can be prepared and filled into a hard gelatincapsule; or a solution of active compound in polyethylene glycol or asuspension in edible oil, for example, liquid paraffin or fractionatedcoconut oil can be prepared and filled into a soft gelatin capsule.

Tablet binders that can be included are acacia, methylcellulose, sodiumcarboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropylmethyl-cellulose, sucrose, starch and ethylcellulose. Lubricants thatcan be used include magnesium stearate or other metallic stearates,stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, cherryflavoring or the like can also be used. Additionally, it may bedesirable to add a coloring agent to make the dosage form moreattractive in appearance or to help identify the product.

Other components suitable for use in the formulations of the presentinvention can be found in Remington's Pharmaceutical Sciences, MacePublishing Company, Philadelphia, Pa., 17th ed. (1985).

Optional Active Agent

In certain embodiments, the identifier is not associated with apharmaceutically active agent. As such, the identifier, and any carrieror other component that make up the ingestible event marker, do notinclude an active agent.

In yet other embodiments, the identifier is associated with an activeagent, e.g., where the active agent is present in the carriercomposition that includes the identifier. By “active agent/carriercomponent” is meant a composition, which may be a solid or fluid (e.g.,liquid), which has an amount of active agent, e.g., a dosage, present ina pharmaceutically acceptable carrier. The active agent/carriercomponent may be referred to as a “dosage formulation.”

“Active agent” includes any compound or mixture of compounds whichproduces a physiological result, e.g., a beneficial or useful result,upon contact with a living organism, e.g., a mammal, such as a human.Active agents are distinguishable from such components as vehicles,carriers, diluents, lubricants, binders and other formulating aids, andencapsulating or otherwise protective components. The active agent maybe any molecule, as well as binding portion or fragment thereof, that iscapable of modulating a biological process in a living subject. Incertain embodiments, the active agent may be a substance used in thediagnosis, treatment, or prevention of a disease or as a component of amedication. In certain embodiments, the active agent may be a chemicalsubstance, such as a narcotic or hallucinogen, which affects the centralnervous system and causes changes in behavior.

The active agent (i.e., drug) is capable of interacting with a target ina living subject. The target may be a number of different types ofnaturally occurring structures, where targets of interest include bothintracellular and extracellular targets. Such targets may be proteins,phospholipids, nucleic acids and the like, where proteins are ofparticular interest. Specific proteinaceous targets of interest include,without limitation, enzymes, e.g., kinases, phosphatases, reductases,cyclooxygenases, proteases and the like, targets comprising domainsinvolved in protein-protein interactions, such as the SH2, SH3, PTB andPDZ domains, structural proteins, e.g., actin, tubulin, etc., membranereceptors, immunoglobulins, e.g., IgE, cell adhesion receptors, such asintegrins, etc., ion channels, transmembrane pumps, transcriptionfactors, signaling proteins, and the like.

The active agent (i.e., drug) may include one or more functional groupsnecessary for structural interaction with the target, e.g., groupsnecessary for hydrophobic, hydrophilic, electrostatic or even covalentinteractions, depending on the particular drug and its intended target.Where the target is a protein, the drug moiety may include functionalgroups necessary for structural interaction with proteins, such ashydrogen bonding, hydrophobic-hydrophobic interactions, electrostaticinteractions, etc., and may include at least an amine, amide,sulfhydryl, carbonyl, hydroxyl or carboxyl group, such as at least twoof the functional chemical groups.

Drugs of interest may include cyclical carbon or heterocyclic structuresand/or aromatic or polyaromatic structures substituted with one or moreof the above functional groups. Also of interest as drug moieties arestructures found among biomolecules, including peptides, saccharides,fatty acids, steroids, purines, pyrimidines, derivatives, structuralanalogs or combinations thereof. Such compounds may be screened toidentify those of interest, where a variety of different screeningprotocols are known in the art.

The active agent may be derived from a naturally occurring or syntheticcompound that may be obtained from a wide variety of sources, includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including the preparation ofrandomized oligonucleotides and oligopeptides. Alternatively, librariesof natural compounds in the form of bacterial, fungal, plant and animalextracts are available or readily produced. Additionally, natural orsynthetically produced libraries and compounds are readily modifiedthrough conventional chemical, physical and biochemical means, and maybe used to produce combinatorial libraries. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification, etc. to producestructural analogs.

As such, the active agent may be obtained from a library of naturallyoccurring or synthetic molecules, including a library of compoundsproduced through combinatorial means, i.e., a compound diversitycombinatorial library. When obtained from such libraries, the drugmoiety employed will have demonstrated some desirable activity in anappropriate screening assay for the activity. Combinatorial libraries,as well as methods for producing and screening such libraries, are knownin the art and described in: U.S. Pat. Nos. 5,741,713; 5,734,018;5,731,423; 5,721,099; 5,708,153; 5,698,673; 5,688,997; 5,688,696;5,684,711; 5,641,862; 5,639,603; 5,593,853; 5,574,656; 5,571,698;5,565,324; 5,549,974; 5,545,568; 5,541,061; 5,525,735; 5,463,564;5,440,016; 5,438,119; 5,223,409, the disclosures of which are hereinincorporated by reference.

Broad categories of active agents of interest include, but are notlimited to: cardiovascular agents; pain-relief agents, e.g., analgesics,anesthetics, anti-inflammatory agents, etc.; nerve-acting agents;chemotherapeutic (e.g., anti-neoplastic) agents; etc.

A variety of manufacturing protocols may be employed to producecompositions as described above, e.g., where an identifier is present inpharmaceutically acceptable carrier or vehicle, where the carrier orvehicle may further include one or more active agents. In manufacturingsuch compositions, an identifier is stably associated with thepharmaceutical dosage from in some manner. By stably associated is meantthat the identifier and the dosage form do not separate from each other,at least until administered to the subject in need thereof, e.g., byingestion. The identifier may be stably associated with thepharmaceutical carrier/active agent component of the composition in anumber of different ways. In certain embodiments, where thecarrier/active agent component is a solid structure, e.g., such as atablet or pill, the carrier/active agent component is produced in amanner that provides a cavity for the identifier. The identifier is thenplaced into the cavity and the cavity sealed, e.g., with a biocompatiblematerial, to produce the final composition. For example, in certainembodiments a tablet is produced with a die that includes a featurewhich produces a cavity in the resultant compressed tablet. Theidentifier is placed into the cavity and the cavity sealed to producethe final tablet. In a variation of this embodiment, the tablet iscompressed with a removable element, e.g., in the shape of a rod orother convenient shape. The removable element is then removed to producea cavity in the tablet. The identifier is placed into the cavity and thecavity sealed to produce the final tablet. In another variation of thisembodiment, a tablet without any cavity is first produced and then acavity is produced in the tablet, e.g., by laser drilling. Theidentifier is placed into the cavity and the cavity sealed to producethe final tablet. In yet other embodiments, a tablet is produced bycombining the identifier with subparts of the tablet, where the subpartsmay be pre-made subparts or manufactured sequentially. For example, incertain embodiments tablets are produced by first making a bottom halfof the tablet, placing the signal generation element on a location ofthe bottom half of the tablet, and then placing top portion of thetablet over the bottom half and signal generation element to produce thefinal desired composition. In certain embodiments, a tablet is producedaround an identifier such that the identifier is located inside of theproduced tablet. For example, an identifier, which may or may not beencapsulated in a biocompatible compliant material, e.g., gelatin (toprotect the signal generation element), is combined with carrier/activeagent precursor, e.g., powder, and compressed or molded into a tablet ina manner such that the identifier is located at an internal position ofthe tablet. Instead of molding or compressing, the carrier/active agentcomponent is, in certain embodiments, sprayed onto an identifier in amanner that builds up the tablet structure. In yet another embodiment,the active agent/carrier component precursor may be a liquid formulationwhich is combined with the identifier and then solidified to produce thefinal composition. In yet other embodiments, pre-made tablets may befitted with an identifier by stably attaching an identifier to thetablet. Of interest are protocols that do not alter the properties ofthe tablet, e.g., dissolution etc. For example, a gelatin element thatsnap fits onto one end of a tablet and has an identifier integrated withit is employed in certain embodiments. The gelatin element is colored incertain embodiments to readily identify tablets that have been fittedwith the signal generation element. Where the composition has an activeagent/carrier composition filled capsule configuration, e.g., such as agelatin capsule filled configuration, an identifier may be integratedwith a capsule component, e.g., top or bottom capsule, and the capsulefilled with the active agent/carrier composition to produce the finalcomposition. The above reviewed methods of manufacture are merelyillustrative of the variety of different ways in which the compositionsof the invention may be manufactured.

In certain embodiments, the identifiers are disrupted uponadministration to a subject. As such, in certain embodiments, thecompositions are physically broken, e.g., dissolved, degraded, eroded,etc., following delivery to a body, e.g., via ingestion, injection, etc.The compositions of these embodiments are distinguished from devicesthat are configured to be ingested and survive transit through thegastrointestinal tract substantially, if not completely, intact.

Systems

Also provided are systems that include the subject compositions. Systemsof the subject invention include, in certain embodiments, one or moredevices that include an in-body power source of the invention, e.g., anidentifier as reviewed above, as well as a signal detection component,e.g., in the form of a receiver. The signal detection component may varysignificantly depending on the nature of the signal that is generated bythe signal generation element of the composition, e.g., as reviewedabove.

Signal receivers of systems of embodiments of the invention are thosethat are configured to receive a signal from an identifier, e.g., toreceive a signal emitted by an identifier upon contact of the identifierwith the target physiological site following ingestion of theidentifier. The signal receiver may vary significantly depending on thenature of the signal that is generated by the signal generation element,e.g., as reviewed below. As such, the signal receiver may be configuredto receive a variety of different types of signals, including but notlimited to: RF signals, magnetic signals, conductive (near field)signals, acoustic signals, etc., as indicated above. In certainembodiments, the receiver is configured to receive a signal conductivelyfrom another component, e.g., the identifier, such that the twocomponents use the body of the patient as a communication medium. Assuch, the signal that is transferred between identifier o and thereceiver travels through the body, and requires the body as theconduction medium. The identifier emitted signal may be transmittedthrough and received from the skin and other body tissues of the subjectbody in the form of electrical alternating current (a.c.) voltagesignals that are conducted through the body tissues. As a result, suchembodiments do not require any additional cable or hard wire connection,or even a radio link connection for transmitting the sensor data fromthe autonomous sensor units to the central transmitting and receivingunit and other components of the system, since the sensor data aredirectly exchanged via the skin and other body tissues of the subject.This communication protocol has the advantage that the receivers may beadaptably arranged at any desired location on the body of the subject,whereby the receivers are automatically connected to the requiredelectrical conductor for achieving the signal transmission, i.e., thesignal transmission is carried out through the electrical conductorprovided by the skin and other body tissues of the subject. In certainembodiments, the signal detection component is one that is activatedupon detection of a signal emitted from an identifier. In certainembodiments, the signal receiver is capable of (i.e., configured to)simultaneously detecting multiple different signals, e.g., 2 or more, 5or more, 10 or more, etc.

The signal receiver may include a variety of different types of signalreceiver elements, where the nature of the receiver element necessarilyvaries depending on the nature of the signal produced by the signalgeneration element. In certain embodiments, the signal receiver mayinclude one or more electrodes (e.g., 2 or more electrodes, 3 or moreelectrodes, includes multiple, e.g., 2 or more, 3 or more, 4 or morepairs of electrodes, etc.) for detecting signal emitted by the signalgeneration element. In certain embodiments, the receiver device will beprovided with two electrodes that are dispersed at a distance, e.g., adistance that allows the electrodes to detect a differential voltage.This distance may vary, and in certain embodiments ranges from about 0.1to about 5 cm, such as from about 0.5 to about 2.5 cm, e.g., about 1 cm.In an alternative embodiment, a receiver that utilizes a singleelectrode is employed. In certain embodiments, the signal detectioncomponent may include one or more coils for detecting signal emitted bythe signal generation element. In certain embodiments, the signaldetection component includes an acoustic detection element for detectingsignal emitted by the signal generation element. In certain embodiments,multiple pairs of electrodes (e.g., as reviewed above) are provided, forexample to increase detection probability of the signal.

The signal receivers of interest include both external and implantablesignal receivers. In external embodiments, the signal receiver is exvivo, by which is meant that the receiver is present outside of the bodyduring use. Where the receiver is implanted, the signal receiver is invivo. The signal receiver is configured to be stably associated with thebody, e.g., either in vivo or ex vivo, at least during the time that itreceives the emitted signal from the IEM.

Signal receivers of interest include, but are not limited to, thosereceivers disclosed in: PCT application serial no. PCT/US2006/016370filed on Apr. 28, 2006 and entitled PHARMA-INFORMATICS SYSTEM; and PCTapplication serial no. PCT/US2008/052845 filed on Feb. 1, 2008 andentitled INGESTIBLE EVENT MARKER SYSTEMS; the disclosures of whichapplications (and particularly signal receiver components thereof) areherein incorporated by reference.

In certain embodiments, the signal receiver is configured to providedata of a received signal to a location external to said subject. Forexample, the signal receiver may be configured to provide data to anexternal data receiver, e.g., which may be in the form of a monitor(such as a bedside monitor), a computer (e.g., PC or MAC), a personaldigital assistant (FDA), phone, messaging device, smart phone, etc. Inone embodiment, if a signal receiver failed to detect a signalindicating that a pill had been ingested, the signal receiver couldtransmit a reminder to take the pill to the subject's PDA or smartphone, which could then provide a prompt to the user to take themedication, e.g., a display or alarm on the FDA, by receiving a phonecall on the smart phone (e.g., a recorded message) etc. The signalreceiver may be configured to retransmit data of a received signal tothe location external to said subject. Alternatively, the signalreceiver according may be configured to be interrogated by an externalinterrogation device to provide data of a received signal to an externallocation.

As such, in certain embodiments the systems include an external devicewhich is distinct from the receiver (which may be implanted or topicallyapplied in certain embodiments), where this external device provides anumber of functionalities. Such an apparatus can include the capacity toprovide feedback and appropriate clinical regulation to the patient.Such a device can take any of a number of forms. By example, the devicecan be configured to sit on the bed next to the patient, e.g., a bedsidemonitor. Other formats include, but are not limited to, PDAs, smartphones, home computers, etc. The device can read out the informationdescribed in more detail in other sections of the subject patentapplication, both from pharmaceutical ingestion reporting and fromphysiological sensing devices, such as is produced internally by apacemaker device or a dedicated implant for detection of the pill. Thepurpose of the external apparatus is to get the data out of the patientand into an external device. One feature of the external apparatus isits ability to provide pharmacologic and physiologic information in aform that can be transmitted through a transmission medium, such as atelephone line, to a remote location such as a clinician or to a centralmonitoring agency.

Methods

Aspects of the invention further include methods of using in-bodydevices that include in-body power sources of the invention. Generally,methods of the invention will include placing the in-body device in somemanner in the body of the subject, e.g., by implanting the device in asubject, by ingesting the device, etc. The devices may be employed witha variety of subjects. Generally such subjects are “mammals” or“mammalian,” where these terms are used broadly to describe organismswhich are within the class mammalia, including the orders carnivore(e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), andprimates (e.g., humans, chimpanzees, and monkeys). In certainembodiments, the subjects will be humans. Following placement of thedevices in the body of a subject, the devices are employed for a varietyof purposes, e.g., to sense one or more physiological parameters, todeliver one or more therapies, to mark a personal event of interest,etc.

In certain embodiments, the in body devices are ingestible devices,where the in body power source is part of an identifier of the device.In such embodiments, the identifier is ingested and a signal emitted bythe identifier is detected, e.g., with a receiver as described above.Such methods are further described in PCT application serial no.PCT/US2006/016370 filed on Apr. 28, 2006 and entitled PHARMA-INFORMATICSSYSTEM; and PCT application serial no. PCT/US2008/052845 filed on Feb.1, 2008 and entitled INGESTIBLE EVENT MARKER SYSTEMS; the disclosures ofwhich applications (and particularly signal receiver components thereof)are herein incorporated by reference.

Utility

Devices that include the in-body power sources of the invention may beemployed in a variety of different applications, including boththerapeutic and non-therapeutic applications. Specific applications ofinterest include, but are not limited to: those applications describedin PCT application serial no. PCT/US2006/016370 filed on Apr. 28, 2006and entitled PHARMA-INFORMATICS SYSTEM; and PCT application serial no.PCT/US2008/052845 filed on Feb. 1, 2008 and entitled INGESTIBLE EVENTMARKER SYSTEMS; the disclosures of which applications (and particularlysignal receiver components thereof) are herein incorporated byreference.

IEM in body devices of the invention may be employed in a variety ofdifferent applications, which applications may be both medical andnon-medical in nature. Different illustrative applications are nowreviewed below in greater detail below.

Certain applications involve the use of IEMs by themselves to mark apersonal event of interest, e.g., onset of a physiological parameter(such as a symptom(s) of interest), onset of an activity, etc. Forexample, in certain embodiments, event markers are employed to mark theonset of a symptom of interest. In such instances, when an individualbecomes aware of a symptom of interest, e.g., begins to feel flushed,nauseous, excited, etc., e.g., the individual may ingest an IEM to markthe occurrence of the symptom of interest. For example, the patient maybegin to not feel well, and ingest an event marker in response to thisill feeling. Upon ingestion, the marker sends a signal to a receiver,which may then record receipt of the signal for further use, e.g., tocombine with physiological data, etc. In certain embodiments, thereceived signal is employed to provide context for any physiologicaldata that is obtained from the patient, e.g., by sensors on thereceiver, from an implantable recorder, etc.

Another symptom of interest is pain. In these embodiments, theingestible event marker may be employed a pain marker. For example,where a patient is being monitored for pain, if a patient feels no pain,the patient may ingest a first type of marker. If the patient feelspain, the patient may ingest a second type of marker. Different types ofmarkers may be differentiated, such as color coded, where desired, toassist in their identification and proper use by the patient. Forexample, markers to be ingested when the patient does not feel pain maybe color coded blue, while markers that are to be ingested with thepatient does have pain may be color coded yellow. Instead of havingdifferent types of markers, a protocol may be employed in which theamount of markers ingested, and therefore the signal obtained, e.g.,from a single marker or two or more markers, is employed to denote scaleof symptom of interest, such as pain. So, if an individual is havingintense pain, the individual takes four of the positive pain pills atthe same time, while in response to mild pain the individual may takeonly one marker.

In such embodiments, the onset of the symptom of interest, as marked bythe ingestion of the event marker and detection of the signal by thereceiver, may be employed as relevant point at which to begin recordingone or more physiological parameters of interest, e.g., by using animplantable physiological monitor. In these instances, the emittedsignal from the marker is received by the receiver, which then causes aphysiological parameter recorder (such as a Reveal® Plus Insertable LoopRecorder (ILR), Medtronic Corporation) to begin recording data andsaving the data, e.g., for later use. For example, an implantablephysiological parameter recorder may have only a limited possible amountof time for recording (such as 42 minutes). In such situations, the datamay be automatically overwritten unless somehow flagged or marked forprotection. In the present methods, an IEM may be ingested to mark theonset of a symptom of interest, as perceived by the patient, andreceiver upon receipt of the signal may act with the recorder to protectthe data obtained around the time of the signal (after, or even sometime before) to be protected and not overwritten. The system may befurther configured to work in response not only to the ingestion of theevent marker, but also in response to physiological sensed parameters,e.g., pH. As such, the methods find use as an event recorder in terms offlagging a diagnostic stream of information, and protecting it frombeing overwritten, so a physician can look at it at a later date.

In certain embodiments, the event marker provides the context forinterpreting a given set of physiological data at a later time. Forexample, if one is employing an activity sensor and one co-administersand event marker with a particular drug, one can note any change inactivity that is brought about by that drug. If a drop in activity isobserved after a person takes both the event marker and a drug, the dropindicates the drug is probably causing the person to reduce theiractivity, e.g., by making them feel sleepy or actually causing them tofall asleep. Such data may be employed to adjust the does of a drug orbe the basis for a decision to switch to an alternative medication.

In certain embodiments the event marker is employed to construct adatabase of multiple events. Such a database may be employed to findcommonality between the multiple marked events. Simple or complexprotocols for finding commonality among multiple marked events may beemployed. For example, multiple events may be averaged. Alternativelytechniques such as impulse response theory may be employed, where suchtechniques provide information on what exactly are the common featuresin a set of multiple sensor streams that are tied to a particular event.

The IEM systems of the invention enable one to use subjective symptoms,such as “I'm feeling funny,” to impart context and background toobtained objective measures of what's really going on physiologically.So, if every time somebody felt abnormal they took an event marker, onecould reference a database of the objective sensor data, and find commonfeatures in the database. Such an approach may be employed to discoverthe underlying causes of the subjective feeling. For example, such anapproach may be employed to determine that every time a person isfeeling funny, they have some change in their blood pressure, and thatlink between a subjective symptom and objective physiological data canbe used in their diagnosis. As such, a generalizable event marker bringscontext to discrete data from any other source. As such, use of the oralmedication event markers provides context for any other associatedhealth monitoring information or health event.

In certain embodiments, the event marker can be an alert marker, suchthat ingestion of the marker causes an alarm signal to be sent from thepatient, e.g., indicating that the patient needs medical assistance. Forexample, when a patient feels an onset of a symptom of interest, such aschest pain, shortness of breath, etc., the patient may ingest an eventmarker. The signal emitted from the event marker may be received by thereceiver, which may then cause an alarm to be generated and distributedto a medical professional.

In certain embodiments, the event marker is employed to instigate orstart a therapeutic action, e.g., activate an implantable pulsegenerator to deliver electrical therapy, activate an implanted drugdelivery device to administer a dosage of drug, activate a physiologicalsensor to begin acquiring data, etc. For example, where a patient has aneural stimulator for treating migraines, upon perception of the onsetof aura, the patient could ingest an IEM. The emitted signal would thenactivate neural stimulator into stimulus mode, and thereby cause theimplant to deliver therapy. Alternatively, if one has an implanted drugdeliver device, e.g., a device that delivers an oncotic agent, ingestionof the IEM could cause the implanted device to deliver the active agent.

In certain embodiments, the event marker is employed to deliverinformation to an implanted medical device in the patient. For example,an ingestible event marker may send a signal that includes update datafor an implanted medical devices, such as firmware upgrade data for animplantable pulse generator, e.g., a pace maker. In such instances, thesignal may include the upgrade code which is broadcast from the IEMconductively to the medical device, where upon receipt of the signal andcode, the firmware of the medical device is upgraded.

Other applications where event markers may be employed by themselves isto mark or note the start of non-medical personal event, such as acommute time, the start of an exercise regimen, sleep time, smoking(e.g., so one can log how much one smokes) etc.

As indicated above, embodiments of the invention are characterized inthat the event markers are co-ingested with another composition ofmatter, e.g., a pharmaceutical composition, food, etc, where the eventmarker may or may not be present in the same composition as theco-ingested matter. For example, the event markers may be employed totrack ingesting a pharmaceutical agent, where one co-administers themarker with the drug of interest. Applications where co-administrationof a drug and marker is of interest include, but are not limited to,clinical studies, titration of medicine, e.g., blood pressure medicine,etc, Where desired, the IEM could be provided as just another pill whenthe fill at the pharmacy essentially.

Instead of co-ingesting the event marker with another composition, e.g.,a drug, food, etc., the marker and the other composition may becompounded together, e.g., by the end user. For example, an IEM in theform of a capsule can be opened by the end user and filled with apharmaceutical composition. The resultant compounded capsule and activeagent may then be ingested by the end user. Instead of an end user, thepharmacist or a health care provided may perform the compounding step.

In yet other embodiments, the marker is present already compounded withthe other composition at the source of manufacture of the othercomposition, e.g., the manufacturer or producer of a pharmaceuticalcomposition. An example of such compositions includes those described inPCT application serial no. PCT/US2006/016370; the disclosure of which isherein incorporated by reference.

In certain embodiments, the IEMs of the invention are employed to allowone to look at, on an individual basis, what a given result is withrespect to what drugs an individual is taking versus their impact onindicators that correlate to the desired effect. For example, where agiven patient is prescribed a regiment of multiple pharmaceutical agentsand there are multiple different physiological parameters that aremonitored as indicators of how the patient is responding to theprescribed therapeutic regimen, a given drug as marked by a given markercan be assessed in terms of its impact on a one or more of thephysiological parameters of interest. Following this assessment,adjustments can be made accordingly. In this manner, automation may beemployed to tailor therapies based on individual responses. For example,where a patient is undergoing oncotic therapy, the event marker can beused to provide real time context to obtained physiological parameterdata. The resultant annotated real time data can be used to makedecisions about whether or not to continue therapy, or change to a newtherapy. In certain embodiments, a dosing event (as marked by the IEM)is correlated with sensor data to develop a profile for how a given drugacts, e.g., in terms of a pharmacokinetic and/or pharmacodynamic model.Sensors are employed with the IEM marking of the dosing event to obtaina pharmacokinetic model. Once one has the pharmacokinetic model, one canuse the dosing event to drive that model and predict serum drug levelsand response. One might find, as determined from various sensors, thatthis patient is not doing so well at this time. One might look back atthe pharmacokinetic model and say the levels of this drug in the bloodare getting low when the patient is sensed as not doing well. This datais then used to make a determination to increase the dosing frequency orincrease the dose at a given dosing event. The event marker provides away to develop a model and then apply it.

Where the IEMs are co-administered with a pharmaceutical agent, e.g., astwo separate compositions or a single composition (as described above),the systems of the invention, such as the one shown in FIG. 12 , enablea dynamic feedback and treatment loop of tracking medication timing andlevels, measuring the response to therapy, and recommending altereddosing based on the physiology and molecular profiles of individualpatients. For example, a symptomatic heart failure patient takesmultiple drugs daily, primarily with the goal of reducing the heart'sworkload and improving patient quality of life. Mainstays of therapyinclude angiotensin converting enzyme (ACE) inhibitors, β-blockers anddiuretics. For pharmaceutical therapy to be effective, it is vital thatpatients adhere to their prescribed regimen, taking the required dose atthe appropriate time. Multiple studies in the clinical literaturedemonstrate that more than 50% of Class II and III heart failurepatients are not receiving guideline-recommended therapy, and, of thosewho are titrated appropriately, only 40-60% adhere to the regimen. Withthe subject systems, heart failure patients can be monitored for patientadherence to therapy, and adherence performance can be linked to keyphysiologic measurements, to facilitate the optimization of therapy byphysicians.

In certain embodiments, the systems of the invention may be employed toobtain an aggregate of information that includes sensor data andadministration data. For example, one can combine the heart rate, therespiration rate, multi-axis acceleration data, something about thefluid status, and something about temperature, and derive indices thatwill inform about the total activity of the subject, that can be used togenerate a physiological index, such as an activity index. For instance,when there is a rise in temperature, heart rate goes up a bit, andrespiration speeds up, which may be employed as an indication that theperson is being active. By calibrating this, the amount of calories theperson is burning at that instant could be determined. In anotherexample, a particular rhythmic set of pulses or multi-axis accelerationdata can indicate that a person is walking up a set of stairs, and fromthat one can infer how much energy they are using. In anotherembodiment, body fat measurement (e.g. from impedance data) could becombined with an activity index generated from a combination of measuredbiomarkers to generate a physiological index useful for management of aweight loss or cardiovascular health program. This information can becombined with cardiac performance indicators to get a good picture ofoverall health, which can be combined with pharmaceutical therapyadministration data. In another embodiment, one might find for examplethat a particular pharmaceutical correlates with a small increase inbody temperature, or a change in the electrocardiogram. One can developa pharmacodynamic model for the metabolism of the drug, and use theinformation from the receiver to essentially fit the free parameters inthat model to give much more accurate estimation of the levels actuallypresent in the serum of the subject. This information could be fed backto dosing regimes. In another embodiment, one can combine informationfrom a sensor that measures uterine contractions (e.g. with a straingauge) and that also monitors fetal heart rate, for use as a high-riskpregnancy monitor.

In certain embodiments, the subject specific information that iscollected using the systems of the invention may be transmitted to alocation where it is combined with data from one or more additionalindividuals to provide a collection of data which is a composite of datacollected from 2 or more, e.g., 5 or more, 10 or more, 25 or more, 50 ormore, 100 or more, 1000 or more, etc., individuals. The composite datacan then be manipulated, e.g., categorized according to differentcriteria, and made available to one or more different types of groups,e.g., patient groups, health care practitioner groups, etc., where themanipulation of data may be such as to limit the access of any givengroup to the type of data that group can access. For example, data canbe collected from 100 different individuals that are suffering from thesame condition and taking the same medication. The data can be processedand employed to develop easy to follow displays regarding patientcompliance with a pharmaceutical dosage regimen and general health.Patient members of the group can access this information and see howtheir compliance matches with other patient members of the group, andwhether they are enjoying the benefits that others are experiencing. Inyet another embodiment, doctors can also be granted access to amanipulation of the composite data to see how their patients arematching up with patients of other doctors, and obtain usefulinformation on how real patients respond to a given therapeutictreatment regiment. Additional functionalities can be provided to thegroups given access to the composite data, where such functionalitiesmay include, but are not limited to: ability to annotate data, chatfunctionalities, security privileges, etc.

The inventive pharmacokinetic model allows for drug dosing regimens tobe adjusted in real time in response to varying serum levels in thebody. The pharmacokinetic model can predict or measure the serum levelof a given medication in the body. This data can then be used tocalculate when the next dose of medication should be taken by thepatient. An alarm can be triggered at that time to alert the patient totake a dose. If the serum level remains high, an alarm can be triggeredto alert the patient not to take the next dose at the originallyprescribed time interval. The pharmacokinetic model can be used inconjunction with a medication ingestion monitoring system that includesan IBM, such as that described above. Data from this system can beincorporated into the model, as well as population data, measured data,and data input by the patient. Utilizing data from multiple sources, avery powerful and accurate tool can be developed.

In some embodiments, the data gathered by the receiver can be useddirectly by the pharmacokinetic model to determine when a medication wasadministered, what medication it was and in what amount. Thisinformation can be used to calculate an estimate of the serum level ofthe medication in the patient. Based on the calculated serum level, thepharmacokinetic model can send an alert to the patient to say eitherthat the serum level is too high and is near or above the toxic level,or that the serum level is too low and they should take another dose.The pharmacokinetic model can be run on the implanted receiver itself oron an external system which receives data from the implanted receiver.

A simple form of the pharmacokinetic model can assume that every patientis the same, and use average population data to model the serum level. Amore complex and more accurate model can be obtained by inputting otherinformation about the patient. This information can be inputted by theuser, such as a physician, or gathered by the receiver from associatedsensors. Information that can be used to adjust the model include othermedications being taken, diseases the patient suffers from, patient'sorgan function, enzyme levels, metabolism, body weight, and age, amongother factors. Information can also be inputted by the patientthemselves, such as if they feel hypoglycemic, or have pain ordizziness. This can be used as further evidence to validate thepredictions of the model.

Examples of food applications include the following. In certain diseaseconditions, such as diabetes, it can be important what a patient ate andwhen. In such instances, event markers of the invention are keyed orlinked to the type of food a patient eats. For example, one can have aset of event markers for different food items, and one can co-administerthem with the food items. From the resultant data, one can do a completeindividual metabolic profile on an individual. One knows how manycalories the patient is consuming. By obtaining activity and heart rateand ambient temperature versus body temperature data, one can calculatehow many calories one is expending. As a result, guidance can beprovided to the patient as to what foods to eat and when. Non diseasepatients may also track food ingestion in this manner. For example,athletes adhering to a strict training diet may employ IEMs to bettermonitor food ingestion and the effect of the food ingestion on one ormore physiological parameters of interest.

As reviewed in the above discussion, IEM systems of the invention finduse in both therapeutic and non-therapeutic applications. In therapeuticapplications, the IEM may or may not be compounded with apharmaceutically active agent. In those embodiments where the IEM iscompounded with active agent, the resultant compounded composition maybe viewed as a pharma-informatics enabled pharmaceutical composition.

In such Pharma-informatics embodiments, an effective amount of acomposition that includes an IEM and an active agent is administered toa subject in need of the active agent present in the composition, where“effective amount” means a dosage sufficient to produce the desiredresult, e.g. an improvement in a disease condition or the symptomsassociated therewith, the accomplishment of a desired physiologicalchange, etc. The amount that is administered may also be viewed as atherapeutically effective amount. A “therapeutically effective amount”means the amount that, when administered to a subject for treating adisease, is sufficient to effect treatment for that disease.

The composition may be administered to the subject using any convenientmeans capable of producing the desired result, where the administrationroute depends, at least in part, on the particular format of thecomposition, e.g., as reviewed above. As reviewed above, thecompositions can be formatted into a variety of formulations fortherapeutic administration, including but not limited to solid, semisolid or liquid, such as tablets, capsules, powders, granules,ointments, solutions, suppositories and injections. As such,administration of the compositions can be achieved in various ways,including, but not limited to: oral, buccal, rectal, parenteral,intraperitoneal, intradermal, transdermal, intracheal, etc.,administration. In pharmaceutical dosage forms, a given composition maybe administered alone or in combination with other pharmaceuticallyactive compounds, e.g., which may also be compositions having signalgeneration elements stably associated therewith.

The subject methods find use in the treatment of a variety of differentconditions, including disease conditions. The specific diseaseconditions treatable by with the subject compositions are as varied asthe types of active agents that can be present in the subjectcompositions. Thus, disease conditions include, but are not limited to:cardiovascular diseases, cellular proliferative diseases, such asneoplastic diseases, autoimmune diseases, hormonal abnormality diseases,infectious diseases, pain management, and the like.

By treatment is meant at least an amelioration of the symptomsassociated with the disease condition afflicting the subject, whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude of a parameter, e.g. symptom, associated with thepathological condition being treated. As such, treatment also includessituations where the pathological condition, or at least symptomsassociated therewith, are completely inhibited, e.g. prevented fromhappening, or stopped, e.g. terminated, such that the subject no longersuffers from the pathological condition, or at least the symptoms thatcharacterize the pathological condition. Accordingly, “treating” or“treatment” of a disease includes preventing the disease from occurringin an animal that may be predisposed to the disease but does not yetexperience or exhibit symptoms of the disease (prophylactic treatment),inhibiting the disease (slowing or arresting its development), providingrelief from the symptoms or side-effects of the disease (includingpalliative treatment), and relieving the disease (causing regression ofthe disease). For the purposes of this invention, a “disease” includespain.

In certain embodiments, the subject methods, as described above, aremethods of managing a disease condition, e.g., over an extended periodof time, such as 1 week or longer, 1 month or longer, 6 months orlonger, 1 year or longer, 2 years or longer, 5 years or longer, etc. Thesubject methods may be employed in conjunction with one or moreadditional disease management protocols, e.g., electrostimulation basedprotocols in cardiovascular disease management, such as pacingprotocols, cardiac resynchronization protocols, etc; lifestyle, such adiet and/or exercise regimens for a variety of different diseaseconditions; etc.

In certain embodiments, the methods include modulating a therapeuticregimen based data obtained from the compositions. For example, data maybe obtained which includes information about patient compliance with aprescribed therapeutic regimen. This data, with or without additionalphysiological data, e.g., obtained using one or more sensors, such asthe sensor devices described above, may be employed, e.g., withappropriate decision tools as desired, to make determinations of whethera given treatment regimen should be maintained or modified in some way,e.g., by modification of a medication regimen and/or implant activityregimen. As such, methods of invention include methods in which atherapeutic regimen is modified based on signals obtained from thecomposition(s).

In certain embodiments, also provided are methods of determining thehistory of a composition of the invention, where the compositionincludes an active agent, an identifier element and a pharmaceuticallyacceptable carrier. In certain embodiments where the identifier emits asignal in response to an interrogation, the identifier is interrogate,e.g., by a wand or other suitable interrogation device, to obtain asignal. The obtained signal is then employed to determine historicalinformation about the composition, e.g., source, chain of custody, etc.

In certain embodiments, a system is employed that is made up of amultiple different IEMs, e.g., 2 or more distinct IEMS, 3 or moredistinct IEMS, 4 or more distinct IEMs, etc., including 5 or more, 7 ormore, 10 or more distinct IEMs. The distinct IEMs may be configured toprovide distinguishable signals, e.g., where the signals may bedistinguishable in terms of nature of the signal itself, in terms oftiming of emission of the signal, etc. For example, each IEM in suchsets may emit a differently coded signal. Alternatively, each IEM may beconfigured to emit the signal at a different physiological target site,e.g., where each IEM is configured to be activated at a different targetphysiological site, e.g., where an first IEM is activated in the mouth,a second is activated in the esophagus, a third is activated in thesmall intestine and a fourth is activated in the large intestine. Suchsets of multiple different distinguishable IEMs find use in a variety ofdifferent applications. For example, where one has the above described 4IEM set, one can use the set in a diagnostic application to determinefunction of the digestive system, e.g., motility through the digestivetract, gastric emptying etc. For example, by noting when each IEM emitsits respective signal, a plot of signal time may be generated from whichinformation regarding digestive tract functioning may be obtained.

The present invention provides the clinician an important new tool intheir therapeutic armamentarium: automatic detection and identificationof pharmaceutical agents actually delivered into the body. Theapplications of this new information device and system are multi-fold.Applications include, but are not limited to: (1) monitoring patientcompliance with prescribed therapeutic regimens; (2) tailoringtherapeutic regimens based on patient compliance; (3) monitoring patientcompliance in clinical trials; (4) monitoring usage of controlledsubstances; and the like. Each of these different illustrativeapplications is reviewed in greater detail below in copending PCTApplication Serial No. PCT/US2006/016370; the disclosure of which isherein incorporated by reference.

Additional applications in which the subject systems find use includethose described in U.S. Pat. No. 6,804,558, the disclosure of which isherein incorporated by reference. For example, the subject systems maybe used in a medical information communication system which permitsmonitoring the performance of an implantable medical device (IMD)implanted within a body of a patient, monitoring the health of thepatient, and/or remotely delivering a therapy to the patient through theIMD. A signal receiver of the invention, e.g., in an external formatsuch as a bandaid or implanted format, communicates with the IMD and iscapable of bi-directional communication with a communication module, amobile telephone and/or a Personal Data Assistant (PDA) located outsidethe patients body. The system may comprise the IMD, the signal receiverwith the communication module and/or a mobile telephone and/or a PDA, aremote computer system, and a communication system capable ofbi-directional communication, where the communication module, the mobiletelephone and/or the PDA are capable of receiving information from theIMD or relaying information thereto via the signal receiver, which isinternal or external to the patient, as reviewed above.

Additional applications in which receivers of the invention may find useinclude, but are not limited to: fertility monitoring, body fatmonitoring, satiety monitoring, satiety control, total blood volumemonitoring, cholesterol monitoring, smoking detecting, etc.

Kits

Also provided are kits that include one or more in-body devices of theinvention. Kits may include one or more in-body devices, e.g., asdescribed above. In those embodiments having multiple in body devices,such may be packaged in a single container, e.g., a single tube, bottle,vial, and the like, or one or more dosage amounts may be individuallypackaged such that certain kits may have more than one container of anin body device. In certain embodiments the kits may also include asignal receiving element, as reviewed above. In certain embodiments, thekits may also include an external monitor device, e.g., as describedabove, which may provide for communication with a remote location, e.g.,a doctor's office, a central facility etc., which obtains and processesdata obtained about the usage of the composition.

The subject kits may also include instructions for how to practice thesubject methods using the components of the kit. The instructions may berecorded on a suitable recording medium or substrate. For example, theinstructions may be printed on a substrate, such as paper or plastic,etc. As such, the instructions may be present in the kits as a packageinsert, in the labeling of the container of the kit or componentsthereof (i.e., associated with the packaging or sub-packaging) etc. Inother embodiments, the instructions are present as an electronic storagedata file present on a suitable computer readable storage medium, e.g.CD-ROM, diskette, etc. In yet other embodiments, the actual instructionsare not present in the kit, but means for obtaining the instructionsfrom a remote source, e.g. via the internee, are provided. An example ofthis embodiment is a kit that includes a web address where theinstructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

Some or all components of the subject kits may be packaged in suitablepackaging to maintain sterility. In many embodiments of the subjectkits, the components of the kit are packaged in a kit containmentelement to make a single, easily handled unit, where the kit containmentelement, e.g., box or analogous structure, may or may not be an airtightcontainer, e.g., to further preserve the sterility of some or all of thecomponents of the kit.

It is to be understood that this invention is not limited to particularembodiments described, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

Certain ranges have been presented herein with numerical values beingpreceded by the term “about.” The term “about” is used herein to provideliteral support for the exact number that it precedes, as well as anumber that is near to or approximately the number that the termprecedes. In determining whether a number is near to or approximately aspecifically recited number, the near or approximating unrecited numbermay be a number which, in the context in which it is presented, providesthe substantial equivalent of the specifically recited number.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

1.-25. (canceled)
 26. A method of producing an identifier, the methodcomprising: providing an electroplating bath with an electroplatingsolution; including one or more additives in the electroplatingsolution; depositing a metal onto a first surface of a solid support, inthe electroplating bath at a mass-transfer limit of the metal; whereinthe one or more additives in the electroplating solution is to generatea desired porosity of the metal when deposited on the first surface;wherein the metal deposited onto the first surface produces a porousunder-layer at the desired porosity to provide a surface areaenhancement; depositing a first active electrode material on the porousunder-layer; depositing a second active electrode material on a secondsurface of the solid support opposite the first surface, wherein thesecond active electrode material is different from the first activeelectrode material; wherein the first and second active electrodematerials provide a voltage potential difference to a circuitry elementvia completion of a battery when the first and second active electrodematerials contact an electrically conductive fluid within a body;wherein the identifier is configured to communicate a conductivelytransmitted signal that employs the body as a conduction medium; andwherein upon application of the voltage potential difference to thecircuitry element, the circuitry element is configured to generate theconductively transmitted signal such that the conductively transmittedsignal is conducted between the circuitry element and a receiver throughtissues of the body.
 27. The method of claim 26, wherein the one or moreadditives includes an acid.
 28. The method of claim 26, wherein the oneor more additives includes a polymer.
 29. The method of claim 28,wherein the polymer is biocompatible such that the polymer is capable ofcoexistence with living tissues without causing harm.
 30. The method ofclaim 28, wherein the polymer is non-immunogenic such that the polymeris does not produce an immune response in the body.
 31. The method ofclaim 28, wherein the polymer is a polyethylene glycol (PEG).
 32. Themethod of claim 26, wherein the one or more additives includes analcohol.
 33. The method of claim 26, wherein the one or more additivesincludes an accelerator to accelerate a deposition rate of the metal.34. The method of claim 26, wherein the one or more additives includes asuppressing additive to physically block the metal from depositing on atleast some of the solid support.
 35. The method of claim 26, wherein theone or more additives includes a suppressing additive and an acceleratorto accelerating additive to accelerate a deposition rate of the metaland to dislodge the suppressing additive from the solid support.
 36. Themethod of claim 26, wherein the electroplating solution is selected tocause the metal to be deposited onto the first surface in a dendriticform.
 37. The method of claim 26, further comprising producing aco-evolution of gas into the electroplating bath to produce blocking gasbubbles at the first surface of the solid support.
 38. The method ofclaim 37, further comprising employing a surface tension agent tocontrol a size of the blocking gas bubbles.
 39. The method of claim 37,Wherein the one or more additives includes an accelerating agent to actin conjunction with the blocking gas bubbles in the electroplating bath.40. The method of claim 26, further comprising producing aself-assembled monolayer of an organic, diazonium containing speciesthat bonds to the first surface of the solid support to physically blockthe metal from at least some of the solid support.
 41. The method ofclaim 26, wherein the metal is a first metal, and the method furthercomprises simultaneously depositing a second metal onto the solidsupport along with the first metal.
 42. The method of claim 41, furthercomprising immersing the solid support into an electrolytic solutionthat causes the second metal to dissolve away, leaving behind a film ofthe first metal on the solid support.
 43. The method of claim 26,further comprising modifying the solid support to electrically remove atleast some of the metal from the solid support.